This invention is a dihydro-benzo[b][1,4]diazepin-2-one derivative of the formula 
The compounds of formula I are metabotropic glutamate receptor antagonists.
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) form the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the group II can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits.
The present invention is a compound of formula I 
wherein
X is a single bond or an ethynediyl group; wherein
when X is a single bond,
R1 is selected from the group consisting of cyano,
halogen,
lower alkyl,
C3-C6-cycloalkyl,
lower alkoxy,
fluoro-lower alkoxy,
fluoro-lower alkyl,
unsubstituted pyrrol-1-yl, and pyrrol-1-yl substituted by between one and three substituents selected from the group consisting of
fluoro, chloro, cyano, xe2x80x94(CH2)1-4-hydroxy, fluoro-lower alkyl, lower alkyl, xe2x80x94(CH2)n-lower alkoxy, xe2x80x94(CH2)nxe2x80x94C(O)Oxe2x80x94Rxe2x80x3, xe2x80x94(CH2)1-4xe2x80x94NRxe2x80x2Rxe2x80x3, hydroxy-lower alkoxy, and xe2x80x94(CH2)nxe2x80x94CONRxe2x80x2Rxe2x80x3, unsubstituted phenyl, and phenyl substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, fluoro-lower alkyl, lower alkoxy, fluoro-lower alkoxy and cyano;
when X is an ethynediyl group,
R1 is unsubstituted phenyl, or phenyl substituted by between one and three substituents
selected from the group consisting of halogen, lower alkyl, fluoro-lower alkyl,
C3-C6-cycloalkyl, lower alkoxy and fluoro-lower alkoxy;
R2 is -selected from the group consisting of NRxe2x80x2Rxe2x80x3, fluoro-lower alkoxy,
unsubstituted 3-oxo-piperazin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, and 3-oxo-piperazin-1-yl, pyrrolidin-1-yl or piperidin-1-yl substituted by Rxe2x80x3;
Rxe2x80x2 is selected from the group consisting of hydrogen,
lower alkyl,
C3-C6-cycloalkyl,
fluoro-lower alkyl and
2-lower alkoxy lower alkyl;
Rxe2x80x3 is selected from the group consisting of hydrogen,
lower alkyl,
C3-C6-cycloalkyl,
fluoro-lower alkyl,
2-lower alkoxy lower alkyl,
xe2x80x94(CH2)2-4-di-lower alkylamino,
xe2x80x94(CH2)2-4-morpholinyl,
(CH2)2-4-pyrrolidinyl,
xe2x80x94(CH2)2-4-piperidinyl and
3-hydroxy-lower alkyl;
Y is xe2x80x94CHxe2x95x90or xe2x95x90Nxe2x80x94;
R3 is selected from the group consisting of halogen,
lower alkyl,
fluoro-lower alkyl,
lower alkoxy,
cyano,
xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94ORxe2x80x3,
xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x3,
unsubstituted five-membered aromatic heterocycle, and a five-membered aromatic heterocycle, substituted by halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano, xe2x80x94(CH2)nxe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94ORxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NRxe2x80x2Rxe2x80x3 lower alkyl, or lower alkyl substituted by a substituent selected from the group consisting of fluoro, hydroxy, lower alkoxy, cyano and carbamoyloxy; and
n is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable addition salt thereof.
It has surprisingly been found that the compounds of formula I are metabotropic glutamate receptor antagonists. Compounds of formula I are distinguished by valuable therapeutic properties.
Objects of the present invention are: compounds of formula I or a pharmaceutically acceptable salt thereof; pharmaceutically active substances and their manufacture the use of a compound of the invention in the control or prevention of illnesses as described above; and the production of pharmaceutical compositions containing a therapeutically effective amount of the compound of formula I in a pharmaceutically acceptable carrier.
The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in absorption, pharmacokinetics in distribution and transport to the brain.
All tautomeric forms of the compounds of the invention are also embraced herewith.
Preferred are compounds of formula I wherein X is a single bond. Exemplarly preferred are compounds, wherein R1 is trifluoromethyl, and especially those wherein R3 is cyano, for example the following compounds:
4-(4-oxo-8-pyrrolidin-1-yl-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile,
4-[8-(cyclopropylmethyl-methyl-amino)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile,
4-[8-(cyclopropylmethyl-amino)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile,
4-[4-oxo-8-(2,2,2-trifluoro-ethoxy)-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile, and
4-[8-(isopropyl-methyl-amino)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile.
Further preferred are compounds, wherein X is a single bond, R1 is trifluoromethyl and R3 is an unsubstituted five-member aromatic heterocycle or a substituted five-membered aromatic heterocycle, substituted by halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano, xe2x80x94(CH2)nxe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94ORxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(NH2)xe2x95x90NRxe2x80x3, hydroxy, lower alkoxy, lower alkylthio, unsubstituted lower alkyl or lower alkyl substituted by fluoro, hydroxy, lower alkoxy, cyano or carbamoyloxy. Examples of such compounds are the following:
7-dimethylamino-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-dimethylamino-4-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo [b][1,4]diazepin-2-one,
7-dimethylamino-4-(3-imidazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-7-(methyl-propyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo [b][1,4]diazepin-2-one,
7-(isobutyl-methyl-amino)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(isopropyl-methyl-amino)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(isobutyl-methyl-amino)-4-(3-{5-[(isopropyl-methyl-amino)-methyl]-[1,2,3]triazol-1-yl}-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(isopropyl-methyl-amino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo [b][1,4]diazepin-2-one,
7-(methyl-propyl-amino)-4-(3-[1,2,3]triazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(isobutyl-methyl-amino)-4-(3-[1,2,3]triazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-(3-imidazol-1-yl-phenyl)-7-isobutylamino-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-dimethylamino-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-dimethylamino-4-[3-(4-hydroxymethyl-oxazol-2-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-7-(methyl-propyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one, and
4-[3-(5-hydroxymethyl-[1,3,4]thiadiazol-2-yl)-phenyl]-7-(methyl-propyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.
Also preferred are compounds, wherein X is a single bond, and R1 is chloro, for example the following compounds:
8-chloro-7-isobutylamino-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
8-chloro-7-(methyl-propyl-amino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
8-chloro-7-(isopropyl-methyl-amino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo [b][1,4]diazepin-2-one,
8-chloro-7-(isobutyl-methyl-amino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
8-chloro-4-[3-(5-dimethylaminomethyl-[1,2,3]triazol- l-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo [b][1,4]diazepin-2-one,
4-[3-(5-azetidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-8-chloro-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(5-azetidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-8-chloro-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo [b][1,4]diazepin-2-one,8-chloro-7-(isobutyl-methyl-amino)-4-[3-(5-piperidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-7-(isopropyl-methyl-amino)-4-(3-{5-[(isopropyl-methyl-amino)-methyl]-[1,2,3]triazol-1-yl}-phenyl)-1,3-dihydro-benzo [b][1,4]diazepin-2-one,8-chloro-4-(3-{5-[-(isobutyl-methyl-amino)-methyl]-[1,2,3]triazol-1-yl}-phenyl)-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-7-isopropylamino-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-7-(isobutyl-methyl-amino)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-4-(3-imidazol-1-yl-phenyl)-7-isobutylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-7-(ethyl-methyl-amino)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihydro-benzo [b][1,4]diazepin-2-one8-chloro-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-7-(methyl-propyl-amino)-1,3-dihydro-benzo [b][1,4]diazepin-2-one
8-chloro-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one
8-chloro-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one
8-chloro-7-(ethyl-methyl-amino)-4-[3-(4-hydroxymethyl-oxazol-2-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one
8-chloro-4-[3-(4-hydroxymethyl-oxazol-2-yl)-phenyl]-7-(methyl-propyl-amino)-1,3-dihydro-benzo [b][1,4]diazepin-2-one
8-chloro-4-[3-(4-hydroxymethyl-oxazol-2-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one, and
8-chloro-4-[3-(4-hydroxymethyl-oxazol-2-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one.
Further preferred are compounds, wherein X is a single bond and R1 is cyano. Examples of such compounds are the following:
8-diethylamino-2-[3-(3-methyl-isoxazol-5-yl)-phenyl]-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-carbonitrile, and
2-[3-(3-methyl-isoxazol-5-yl)-phenyl]-4-oxo-8-piperidin-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepine-7-carbonitrile.
Also, preferred are further those compounds of formula I, wherein R3 is an unsubstituted five-membered aromatic heterocycle, or a five-membered heterocycle substituted by halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano, xe2x80x94(CH2)nxe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94ORxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(NH2)xe2x95x90NRxe2x80x3, hydroxy, lower alkoxy, lower alkylthio, unsubstituted lower alkyl, or lower alkyl substituted by fluoro, hydroxy, lower alkoxy, cyano or carbamoyloxy.
Especially preferred are those compounds of formula I, wherein R3 is an unsubstituted or substituted five-membered aromatic heterocycle selected from the group consisting of thiazolyl, oxazolyl, isoxazolyl, imidazolyl, 2H-pyrazolyl, [1,2,3 triazolyl, [1,2,4]triazolyl, [1,3,4]thiadiazolyl and [1,3,4]oxadiazolyl. Examples of such compounds are the following:
7-dimethylamino-8-phenylethynyl-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
8-(2-fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-7-(2,2,2-trifluoro-ethoxy)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(ethyl-methyl-amino)-8-methyl-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-dimethylamino-8-methyl-4-[3-(3-methyl-isoxazol-5-yl)-phenyl)-]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(isobutyl-methyl-amino)-8-methyl-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-benzo [b][1,4]diazepin-2-one,
7-(isobutyl-methyl-amino)-8-methyl-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo [b][1,4]diazepin-2-one, and
4-(3-{5-[(cyclopropylmethyl-amino)-methyl]-[1,2,3 ]triazol-1-yl }-phenyl) (isobutyl-methyl-amino)-8-methyl-1,3-dihydro-benzo [b][1,4 ]diazepin-2-one.
Additionally, preferred are compounds of formula I, wherein R2 is xe2x80x94N(CH3)2 or pyrrolidine. Also preferred are compounds, wherein R2 is isopropyl-amino, isopropyl-methyl-amino, isobutyl-amino or isobutyl-methyl-amino.
Also, preferred compounds of formula I in the scope of the present invention are those, wherein R3 is cyano or an unsubstituted five-membered aromatic heterocycle, or a five-member aromatic heterocycle substituted by xe2x80x94CH2OH or xe2x80x94CH2N(CH3)2.
The term xe2x80x9clower alkylxe2x80x9d used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a lower alkyl residue in the sense of the foregoing definition bound via an oxygen atom. Examples of xe2x80x9clower alkoxyxe2x80x9d residues include methoxy, ethoxy, isopropoxy and the like.
The term xe2x80x9chalogenxe2x80x9d embraces fluorine, chlorine, bromine and iodine.
The term xe2x80x9cfluoro-lower alkylxe2x80x9d means a lower alkyl residue, wherein at least one hydrogenxe2x80x94atom is replaced by fluoro.
The term xe2x80x9cfluoro-lower alkoxyxe2x80x9d denotes a lower alkoxy residue in the sense of the definition herein before, wherein at least one hydrogenxe2x80x94atom is replaced by fluoro.
The term xe2x80x9cC3-C6-cycloalkylxe2x80x9d means a cycloalkyl group containing 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term xe2x80x9clower alkylthioxe2x80x9d denotes a lower alkyl residue in the sense of the foregoing definition bound via a sulfur atom, for example methylsulfanyl.
The expression xe2x80x9cfive-membered aromatic heterocyclexe2x80x9d embraces furane, thiophene, thiazole, pyrrole, imidazole, pyrazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole and tetrazole. Preferred five-membered aromatic heterocycles are 1,2,3-triazole, 1,2,4-triazole, isoxazole, 1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole or imidazole.
Substitutedxe2x80x9d means that a group is substituted with at least one, preferably one or two substituents independently selected from the specified group. The term xe2x80x9cunsubstitutedxe2x80x9d in this document is consistent with the generally accepted usage of this term.
The term xe2x80x9cpharmaceutically acceptable addition saltxe2x80x9d refers to any salt derived from a pharamaceutically acceptable inorganic or organic acid or base.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured according to methods, which process comprises reacting a compound of formula II 
with a compound of formula IV or IVa 
wherein R is alkyl, preferably ethyl or butyl, forming a compound of formula III 
then deprotecting the amino group and cyclizing, forming a compound of formula 
wherein R1, R2, R3, X and Y are as described above. A pharmaceutically acceptable addition salt is formed as described above by reacting the compound with a pharmaceutically acceptable organic or inorganic acid or base. 
According to scheme A, compounds of formula I, in which X, Y, R1, R2 and R3 are as described above, can be prepared from compounds of formula II via an acylation-deprotection-cyclization sequence:
For example reacting compounds of formula II with a dioxinone IV, in which Y and R3 are as described above, in an inert solvent such as toluene or xylene at elevated temperatures, preferably between 80xc2x0 C. and 160xc2x0 C. gives rise to compounds of formula III.
Alternatively, compounds of formula III can also be prepared by for example reaction of a compound of formula II with a xcex2-ketoester (formula IVa), in which Y and R3 are as described above using the same conditions as described for the reaction with the dioxinones.
Afterwards, cleaving the BOC protecting group in compounds of formula III and concomitant cyclization of the deprotected compound yields the desired compounds of formula I. Any other suitable amino protecting group, such as e.g. Fmoc or benzyloxycarbonyl (Z), can be alternatively used instead of the BOC group.
The deprotection-cyclization step can be carried out by treating the compounds of formula III with for example a Bronsted acid such as trifluoroacetic acid in an inert solvent such as dichloromethane (DCM). The reaction is preferably carried out at temperatures between 0xc2x0 C. and 50xc2x0 C. It may be advantageous to use also anisole or 1,3-dimethoxybenzene as a carbocation scavenger in the reaction mixture. 
According to scheme B, compounds of formula II in which R1 is phenyl optionally substituted as described above for compounds where X is a single bond and R2 is as described above, can be prepared by different routes depending on the nature of R1 from the iodo-compounds of formula V, in which R2 is as described above. As shown in scheme B, the key step is a coupling reaction of Suzuki-type to produce compounds of the formula VIa.
Compounds of formula II, in which R1, R2 and X are as described above can be prepared according to scheme B, by reducing the nitro group in compounds of formula VIa to the amino group. The reduction can for example be carried out using hydrogen gas in presence of a suitable catalyst like for example Raney-Nickel or Palladium on carbon. Another possible reduction method is using stannous (II) chloride (SnCl2.2H2O) in ethanol at temperatures between 70xc2x0 C. and 80xc2x0 C. (as described in Tetrahedron Lett. 1984, 25, 839), or alternatively in polar aprotic solvents, like DMF, DMA or NMP and the like, optionally in the presence of bases, like for example pyridine or triethylamine and the like, at temperatures between 0xc2x0 C. and 80xc2x0 C. Another suitable method is using zinc-powder in the presence of ammonium chloride in protic solvents like for example water or ethanol at temperatures between 20xc2x0 C. and 80xc2x0 C. The exact conditions for the respective compounds of formula II can be found in the experimental part.
Compounds of formula V, in which R2 is as described above, can be prepared by different routes depending on the individual residue R2: 
As shown in scheme C, compound B1 can be prepared from the commercially available 5-chloro-2-nitroaniline by iodination to give the synthetic intermediate A1, which in turn can be protected to yield the compound B1.
The iodination step can be carried out by for example using iodine monochloride in acetic acid in the presence of sodium acetate. The reaction can be for example carried out at temperatures between 20xc2x0 C. and 80xc2x0 C.
The protection of the amino function can be applied to a number of commercially available starting materials or compounds synthesized by anyone skilled in the art to produce the corresponding 2-nitroanilines with the formula VII, in which X is a single bond and R1 is as described above. This transformation leads to the key intermediates of the formula VIb, and the exact conditions for the respective compounds used in this invention can be found in the experimental part.
One possibility for the protection of the amino function is for example reacting compounds of formula VII with di-tert.-butyl-carbonate in the presence of a base such as cesium carbonate. The reaction can be carried out in polar solvents such as acetone or butanone and the like at temperatures between 20xc2x0 C. and 60xc2x0 C.
Alternatively, the protection of the amino group can be achieved by preparing the intermediate isocyanate by treatment of compounds of the formula VII with diphosgene, preferably in aprotic solvents such as ethyl acetate or 1,4-dioxane at temperatures from 0xc2x0 C. to 100xc2x0 C., and subsequent treatment of the isocyanate with tert.butanol in solvents such as dichloromethane or 1,2-dichloroethane and the like at temperatures between 20xc2x0 C. and 85xc2x0 C. to give the desired compounds of formula VIb.
Another suitable method to achieve this protection step is the intermediate formation of a di-BOC compound by treatment of compounds of the formula VII with di-tert.-butyl-carbonate in the presence of DMAP in an aprotic solvent such as tetrahydrofuran and the like, followed by selective removal of a single BOC-group by treatment with a Bronsted-acid, like e.g. TFA, in aprotic solvents such as dichloromethane, chloroform or 1,2-dichloroethane at temperatures between 0xc2x0 C. and 20xc2x0 C. to give the desired compounds of formula VIb.
According to scheme D, compounds of formula VII in which R1 is pyrrol-1-yl optionally substituted as described above, X is a single bond and R is chloride, can be prepared from known 5-chloro-2-nitro-1,4-phenylenediamine [CAS-No. 26196-45-2] by selective condensation of the 4-amino-group with a suitable substituted 2,5-dimethoxytetrahydrofuran with the formula VIII, as described in J. Heterocycl. Chem. 1988, 25, 1003. 
The reaction is preferably carried out in acidic media, like for example acetic acid or propionic acid and the like, at temperatures between 40xc2x0 C. to 100xc2x0 C. The exact conditions for the respective compounds can be found in the experimental part.
The corresponding substituted 2,5-dimethoxytetrahydrofurans with the formula VIII, in which Ra, Rb and Rc are selected from the group consisting of fluoro, chloro, cyano, xe2x80x94(CH2)1-4-hydroxy, fluoro-lower alkyl, lower alkyl, xe2x80x94(CH2)n-lower alkoxy, xe2x80x94(CH2)nxe2x80x94C(O)Oxe2x80x94Rxe2x80x3, xe2x80x94(CH2)1-4xe2x80x94NRxe2x80x2Rxe2x80x3, hydroxy-lower alkoxy, and xe2x80x94(CH2)nxe2x80x94CONRxe2x80x2Rxe2x80x3, are either commercially available, or synthesized from the suitable substituted furan, as shown in scheme E. The corresponding substituents can optionally be protected with suitable protecting groups, known to someone skilled in the art, or alternatively can be introduced after the pyrrol ring synthesis. The two-step sequence consists of reacting the furan with bromine in MeOH at low temperature, like for example xe2x88x9235xc2x0 C., followed by treatment with base, like for example triethylamine and the like or potassium carbonate or sodium hydrogen carbonate and the like. The resulting 2,5-dimethoxydihydrofuran with the formula VIII, in which Ra, Rb and Rc are as described above, can be reduced by catalytic hydrogenation, preferably in MeOH with catalysts like for example Palladium on carbon or Raney-Nickel and the like, to produce the desired 2,5-dimethoxytetrahydrofurans with the formula VIII. An example for this sequence can be found in Tetrahedron 1971, 27, 1973-1996. 
The exact conditions for the individual compounds to be synthesized can be found in the experimental part.
As shown in scheme F, compounds of formula VIc, in which R2 is attached via a nitrogen-atom and is as described above, can be prepared from the intermediate compounds with the formula VIbxe2x80x94which individual synthesis can be found in the experimental partxe2x80x94by a nucleophilic substitution reaction with the respective amines in the presence of a suitable base. 
The reaction is preferably carried out in a polar, aprotic solvent such as dimethyl formamide, N-methyl-pyrrolidone or dimethyl sulfoxide and the like. The base can be selected from the sterically hindered amines such as triethylamine or Hunig""s base, alkoxides such as sodium methoxide and tert.-butoxide, or hydrides such as sodium hydride. The reaction can be performed at temperatures between 20xc2x0 C. and 110xc2x0 C., depending on the individual compounds to be synthesized. 
According to scheme G, compounds of formula II in which R1 is as described above for compounds where X is an ethynediyl group can be prepared by different routes from the iodo-compounds V, depending on the nature of R1 and R2 As shown in scheme G, the transformation can for example be carried out by directly attaching the R1-alkynediyl-substituent to a compound of formula V via a Sonogashira-type coupling to produce compounds of the formula VId followed by the reduction of the nitro group or by two stepwise Sonogashira-type couplings, in which first trimethylsilyl-acetylene is coupled to a compound of formula V to yield, after desilylation with sodium hydroxide in methanol, the intermediate X which then can be transformed via a second Sonogashira-type coupling with the appropriate reactant R1xe2x80x94I, R1xe2x80x94Br or R1xe2x80x94OSO2CF3 into compounds of the formula VId and reduction of the nitro group leads to the desired compounds of formula II.
The exact conditions for the respective compounds can be found in the experimental part. 
According to Scheme H, the dioxinones and 9-keto esters building blocks with the formula IV and IVa can be prepared by methods known to someone skilled in the art from the corresponding carboxylic acid derivatives R3xe2x80x94COR, i.e. free acids, methyl or ethyl esters and acid chlorides. The exact conditions for the corresponding compounds can be found in the experimental part.
The pharmaceutically acceptable salts can be manufactured readily according to known methods, taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I.
The compounds of formula I and their pharmaceutically acceptable salts are metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are acute and chronic pain, Huntington""s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The compounds of formula I or pharmaceutically acceptable salts thereof can be used as pharmaceutical compositions, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I or pharmaceutically acceptable salts thereof can be processed with pharmaceutically acceptable and therapeutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert, i.e., pharmaceutically acceptable, excipient are also an object of the present invention, as is a process for the production of such pharmaceutical compositions which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
The present invention includes the use of compounds of formula I and of pharmaceutically acceptable salts thereof for the production of pharmaceutical compositions, especially for the control or prevention of acute and/or chronic neurological disorders of the aforementioned kind.
The compounds of the present invention are group II mGlu receptor antagonists. The compounds show Ki values, as measured in the assay described below, of 10 xcexcM or less, typically 1 xcexcM or less, and ideally of 0.3 xcexcM or less.
In Table I below some specific Ki values of preferred compounds of the invention are presented. These values were obtained by indirect measurement of the affinity of the compounds for the recombinant rat mGluR2 expressed in CHO cells using a displacement binding assay with 3H-LY354740.
[3H]-LY354740 Binding on mGlu2 Transfected CHO Cell Membranes
Transfection and Cell Culture
cDNA encoding the rat mGlu2 receptor protein in pBluescript II was obtained from Prof. S. Nakanishi (Kyoto, Japan), and subcloned into the eukaryotic expression vector pcDNA I-amp from Invitrogen (NV Leek, The Netherlands). This vector construct (pcD1mGR2) was co-transfected with a psvNeo plasmid encoding the gene for neomycin resistance, into CHO cells by a modified calcium phosphate method described by Chen and Okayama (1988). The cells were maintained in Dulbecco""s Modified Eagle medium with reduced L-glutamine (2 mM final concentration) and 10% dialysed foetal calf serum from Gibco BRL (Basel, Switzerland). Selection was made in the presence of G-418 (1000 ug/ml final). Clones were identified by reverse transcription of 5 xcexcg total RNA, followed by PCR using mGlu2 receptor specific primers 5xe2x80x2-atcactgcttgggtttctggcactg-3xe2x80x2 and 5xe2x80x2-agcatcactgtgggtggcataggagc-3xe2x80x2 in 60 mM Tris HCl (pH 10), 15 mM (NH4)2SO4, 2 mM MgCl2, 25 units/ml Taq Polymerase with 30 cycles annealing at 60xc2x0 C. for 1 min., extention at 72xc2x0 C. for 30 s, and 1 min. 95xc2x0 C. denaturation.
Membrane Preparation
Cells, cultured as above, were harvested and washed three times with cold PBS and frozen at xe2x88x9280xc2x0 C. The pellet was resuspended in cold 20 mM HEPES-NaOH buffer containing 10 mM EDTA (pH 7.4), and homogenised with a polytron (Kinematica, AG, Littau, Switzerland) for 10 s at 10 000 rpm. After centrifugation for 30 min. at 4xc2x0 C., the pellet was washed once with the same buffer, and once with cold 20 mM HEPES-NaOH buffer containing 0.1 mM EDTA, (pH 7.4). Protein content was measured using the Pierce method (Socochim, Lausanne, Switzerland) using bovine serum albumin as standard.
[3H]-LY354740 Binding
After thawing, the membranes were resuspended in cold 50 mM Tris-HCl buffer containing 2 mM MgCl2 and 2 mM CaCl2, (pH 7) (binding buffer). The final concentration of the membranes in the assays was 25 pg protein/ml. Inhibition experiments were performed with membranes incubated with 10 nM [3H]-LY354740 at room temperature, for 1 hour, in presence of various concentrations of the compound to be tested. Following the incubations, membranes were filtered onto Whatmann GF/C glass fiber filters and washed 5 times with cold binding buffer. Non specific binding was measured in the presence of 10 xcexcM DCG IV. After transfer of the filters into plastic vials containing 10 ml of Ultima-gold scintillation fluid (Packard, Zxc3xcrich, Switzerland), the radioactivity was measured by liquid scintillation in a Tri-Carb 2500 TR counter (Packard, Zxc3xcrich, Switzerland).
Data Analysis
The inhibition curves were fitted with a four parameter logistic equation giving IC50 values, and Hill coefficients and the Ki values were calculated using the Cheng and Prusoff equation (Cheng, Y. and Prusoff, W. H., Biochem. Pharmacol. 1973, 22, 3099-3108). A small Ki value expresses high affinity of the compound towards the receptor.